DESCRIPTION: Several recent studies suggest that there is a fundamental relationship between blood flow and secretory function in salivary glands, and it has been posited that salivary hypofunction in diabetic patients, results in part from abnormalities in blood flow. Neural regulation of submandibular gland (SMG) blood flow is compromised in streptozotocin-diabetic rats, and endothelium-dependent mechanisms appear to play a significant role in this phenomenon. Endothelial cells regulate vascular tone via the synthesis of both relaxing (nitric oxide [NO], prostacyclins and endothelium-derived hyperpolarizing factor [EDHF]) and constricting (endothelin-1 [ET-1] and prostanoids) factors. Further, impaired NO and/or EDHF mediated vasorelaxation and enhanced ET-1 mediated vasoconstriction have both been posited to play a role in the development of microvascular disease in diabetes. The Goals of this application are to: 1. Characterize the physiological relationship between blood flow and salivary secretion in normal and diabetic rats using laser Doppler flowmetry and direct nerve stimulation. The advantages of this approach include a) non-invasive measurement of blood flow, b) approximation of physiological neurotransmitter release and c) concurrent monitoring of salivary secretion and blood flow. Models of both insulin-dependent and non-insulin-dependent diabetes mellitus will be studied. Because gender influences endothelial cell function, we will examine SMG blood flow in both male and female rats. 2. Determine the relative contributions of NO, prostacylins, EDHF and ET-1 to impaired vasodilatation in the diabetic SMG. 3. Specifically investigate the correlation between impaired vasodilatation and endothelial expression of NO synthase (eNOS), ET-1 and the betaI and betaII isoforms of protein kinase C. Gene and protein expression will be assessed by real-time RT-PCR, Western blotting and immunocytochemistry. These studies will add significantly to understanding of salivary gland physiology. In addition, identification of the cellular mechanisms underlying microvascular abnormalities in the diabetic SMG may have important implications for the development of new therapeutic strategies Aimed at the prevention and treatment of diabetic microvascular disease.